Tautomycetin suppresses the TNFalpha/NF-kappaB pathway via inhibition of IKK activation.
TNFalpha activated NF-kappaB and associated regulatory factors including IKK are strongly implicated in a variety of hematological and solid tumor malignancies. We show that tautomycetin (TC) specifically inhibits activation of NF-kappaB among the three TNFalpha effectors (NF-kappaB, JNK and caspase). TC inhibited T-loop phosphorylation of IKKalpha and IKKbeta, thereby preventing degradation of the NF-kappaB inhibitor, IkappaBalpha. Co-immunoprecipitation experiments revealed that the catalytic subunit of PP1 (PP1C) was involved in the IKK complex. Pull-down analysis using recombinant GST-TNFalpha, showed that PP1C was recruited to TNFR1 together with IKK complex, RIP and TAK1 upon stimulus. These results suggest that the PP1 positively regulates the TNFalpha-induced NF-kappaB pathway at the level of IKK activation. Thus, TC might be used therapeutically to suppress the TNFalpha/NF-kappaB pathway.
Mitsuhashi
Shinya
S
Division of Biochemical Oncology and Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo 060-0815, Japan.
Shima
Hiroshi
H
Li
Ying
Y
Tanuma
Nobuhiro
N
Okamoto
Takashi
T
Kikuchi
Kunimi
K
Ubukata
Makoto
M
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008055:Lipids / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D005663:Furans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D008055:Lipids; D020930:MAP Kinase Kinase Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D054645:Protein Phosphatase 1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C000606204:NFKBIA protein, human; C058744:tautomycetin